ABSTRACT Xylyx Bio is developing an innovative biomimetic lung-derived extracellular matrix (ECM) foam sealant material that effectively seals and supports tissue healing for pulmonary air leaks after lung surgery and thoracic trauma. Pulmonary air leak is one of the most common complications after lung surgery, leading to extended chest tube drainage time, patient pain and immobilization, increased risk of infection and bronchopleural fistulae, and subsequent longer hospital stay, with higher associated healthcare costs. In the US alone, over 400,000 patients are at risk for developing pulmonary air leaks every year. Despite the high risk, incidence, and cost of post-surgical pulmonary air leaks, an effective lung sealant is not available. Several synthetic and naturally-derived materials have been tested, but none achieve the required tensile strength, elasticity, adhesive strength and burst pressure resistance for reliably sealing and healing air leaks, thus leaving a significant unmet need. This Phase I SBIR will develop, demonstrate performance, and assess biocompatibility/systemic response of a biomimetic foam sealant comprised of lung ECM that both seals and heals pulmonary air leaks, filling a known gap in therapeutic options for treating and managing air leaks. The technological innovation is the demonstrably novel, unique ?lung-mimetic? foam sealant features ? porous (alveolar-like) structure, mechanics, and bioactivity ? that enable rapid sealing and active lung tissue healing, and the proprietary methods for isolating/processing lung ECM and formulating the sealant. The long-term goal is to develop a lung-mimetic sealant that rapidly seals and heals pulmonary air leaks, leading to reduction of recovery time, postoperative complications, and healthcare costs. The Phase I hypothesis is that a lung-mimetic sealant comprised of lung tissue-derived ECM components with elastic modulus and porosity similar to those of lung tissue can effectively seal and repair air leaks, with excellent biocompatibility, appropriate biodegradation rate, and immunologic response that supports wound healing. Specific aims are to establish lung sealant formulation that results in the desired lung-mimetic features, demonstrate sealant performance in an ex-vivo swine lung model, and assess biocompatibility and systemic response to the foam sealant in a rat model. After Phase I aims are accomplished, demonstrating safety and efficacy in a large animal long-term survival model will be essential for development towards commercialization. Thus, in Phase II, we will assess sealant performance and wound healing in a chronic swine model to inform a preliminary draft of 510(k) premarket notification. Xylyx Bio will then work towards making a lung-mimetic lung sealant commercially available to surgeons in need of a reliable, effective lung sealant to reduce costs to the health care system and improve outcomes for patients recovering from lung surgery and thoracic trauma.